This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Programmed cell death (PCD) is both an important physiological process and a significant anti-tumor defense mechanism in multicellular organisms. Some have even called the ability to evade programmed cell death a "hallmark of cancer". The budding yeast, Saccharomyces cerevisiae, has served as a useful model for complex physiological processes of metazoan cells including PCD. Much work has gone into attempting to describe the molecular mechanisms that drive programmed cell death. For the past four years, my laboratory at Providence College has studied UTH1 and BXI1, two genes linked with programmed cell death in yeast. We have generated mutants lacking UTH1 and BXI1 and have shown that they have phenotypes linking them to the cell wall and the unfolded protein response respectively. This proposal outlines genetic strategies to identify the molecular pathways involved in UTH1 and BXI1 function. It will exploit the primary advantage of the yeast system over its mammalian counterpart as a model system for programmed cell death: Yeast cells are amenable to genetic analysis that allows investigators to identify rapidly molecular pathways underlying a biological process. The genetic strategies described in this proposal will seek to clarify the genetic relationships between UTH1, BXI1, and other PCD genes in yeast to identify the molecular pathways that regulate programmed cell death in this organism. Given the remarkable conservation of the apoptotic pathways across diverse species, this analysis should lead to further insights into the analogous processes in higher organisms including human beings.